Abstract The rotavirus vaccines RotaTeq(R) (Rotavirus Vaccine, live, oral, pentavalent) [RV5] (Merck & Co., Inc.) and Rotarix(R) (Rotavirus Vaccine, live, oral) [RV1] (GlaxoSmithKline Biologicals) are recommended for routine use among U.S. infants by the Advisory Committee on Immunization Practices (ACIP). Recent observational studies suggest that rotavirus vaccines dramatically reduce hospitalizations and emergency department visits among young children in the U.S.; however, there are currently no large-scale studies comparing the effectiveness and safety of RV5 and RV1. We propose to compare the effectiveness and safety of RV5 and RV1 in a population of over 700,000 infants in the U.S. who were covered by private insurance or Medicaid insurance from 2006-2011.The large size of our study will allow us to characterize small differences between the two rotavirus vaccines with regards to effectiveness, which may differ as RV5 requires three administrations versus two for RV1. Our novel self-controlled design and data-driven vaccine surveillance methods will help us further characterize the potential risks linked to rotavirus vaccination intussusception as well as identify other potential conditions of concern. In addition to comparative effectiveness and safety analyses, we will study coverage patterns of both vaccines, including geographic disparities and differences in completion of the rotavirus vaccination series. We will further determine individual, provider, and ecological predictors of rotavirus vaccine uptake. Our research will be conducted with guidance from a panel of experts and stakeholders from the University of North Carolina at Chapel Hill, Harvard School of Public Health, and the Center Biologics Evaluation and Research at the U.S. Food and Drug Administration (FDA). The results of our research will help inform potential quality improvement initiatives by identifying predictors of rotavirus vaccine uptake and will provide clinicians, payors, regulators, and policy makers with timely information on the relative benefits and harms of RV5 versus RV1. The study will also contribute to the development of modern statistical methods and study designs that can be used to study of benefits and risks associated with childhood vaccines.